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The N7-methylguanosine (m7G) cap is the defining structural feature of eukaryotie mRNA that is required for efficient pre-mRNA splicing, export, stability and translation.Eukaryotie viruses that replicate in the cytoplasm, including coronaviruses, have evolved diversified strategies to cap their RNAs.Although the presence of a cap structure at the 5-end of coronavirus RNAs has been known for almost three decades, the mechanisms and viral proteins involved in generating the m7G cap have not been characterized.In our previous work, we employed a yeast genetic system to functionally screen for the capping-forming enzymes encoded by severe acute respiratory syndrome (SARS).eoronavirus (SARS-CoV) and found that the SARS-CoV non-structural protein nsp14 could complement the N7methyltransferase (N7-MTase) activity in vivo in yeast cells.By structural-functional analysis of nsp 14, the N7-MTase domain was mapped to the C-terminal part and ExoN domain to the N-terminal part of nsp14, but neither of the terminal parts alone showed enzymatic activity.By using yeast genetic system and biochemical assays, critical residues were identified for N7-MTase and ExoN.The discovery that the N7-MTase is physically and functionally linked with ExoN suggests that coronavirus nsp14 may represent a novel form of RNA-proeessing enzymes and can thus be used as an attractive drug target to develop antivirals for control of coronaviruses including the deadly SARS-CoV.We further confirmed that the nspl6 2-O methyltransferase requires nsp10 as co-factor for its enzymatic activity.We crystallized the nsp16/nsp10 protein complex, and the atomic structure and biochemical assays revealed that the nsp 10 may stabilize the methyl donor SAM-binding pocket of nsp 16, thus promoting the enzymatic activity of nsp16.We further designed short peptides which were shown to be able to inhibit nsp16/nsp10 MTase activity, thus indicating that nsp16/nsp10 complex may be used as a drug target to screen for anti-coronavirus compounds.